Obesity is a world-wide epidemic, affecting over 400 million adults. This disease is a leading contributor to metabolic disorders such as insulin resistance and Type 2 diabetes and has a significant negative impact on cancer and heart disease. Recent studies from our laboratory indicate that expression and activity of the protein kinase IKKi is markedly up regulated in mice fed a high fat diet (HFD). In mice with a targeted deletion of the IKKi gene we demonstrated an attenuation of the deleterious metabolic effects of high fat feeding. These mice were protected from weight gain, whole body insulin resistance, hepatic steatosis and chronic low-grade inflammation. However, it still remains to be determined the exact tissue sites, initiating signals, and substrates of IKKi that mediate the detrimental consequences of a high-fat diet. We have demonstrated that IKKi expression is specifically increased in liver, and further that there are numerous HFD-induced changes in hepatic gene expression that are reversed in IKKi KO mice. Given the liver's primary role in metabolic regulation, I propose to explore the hepatic- specific role of IKKi as a link between obesity and insulin resistance. The long-term goal of this project is to determine the hepatic-specific mechanism of IKKi and evaluate its therapeutic potential. PUBLIC HEALTH RELEVANCE: Obesity is a complex disease that can lead to serious medical complications, however, the signals that initiate the development of obesity-related complication, in particular diabetes, are not well known. In this project we aim to determine the primary step(s) involved in the development of obesity and how obesity contributes to the development of Type 2 Diabetes.